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Signaling by cell surface receptors and heterotrimeric guanine nucleotide–binding proteins (G proteins) is one of the most exhaustively studied processes in the cell but remains a major focus of molecular pharmacology research. The pheromone-response system in yeast (see the Connections Map at Science's Signal Transduction Knowledge Environment) has provided numerous major advances in our understanding of G protein signaling and regulation. However, the basic features of this prototypical pathway have remained largely unchanged since the mid-1990s. New tools available in yeast are beginning to uncover new pathway components and interactions and have revealed signaling in unexpected locations within the cell.